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Composition of Exendin-4 derivative and preparation method and application thereof

A technology of derivatives and complexes, applied in the field of peptide or protein modification complexes and their preparation, can solve problems such as inhomogeneity of polyethylene glycol modified products, reduced biological activity of modified products, and difficulties in separating and purifying products, achieving Improve bioavailability, not easy to hydrolyze and separate, and easy to obtain raw materials

Inactive Publication Date: 2011-11-09
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the modification of Exendin-4 is mostly multi-point modification, the product has polymorphism, it is difficult to separate and purify the product, and the biological activity of the modified product is reduced
In view of the fact that the time of exendin-4 and its derivatives’ hypoglycemic activity in vivo needs to be further extended, and the products of ordinary polyethylene glycol modification are not uniform, it is urgent to develop a longer time of hypoglycemic activity in vivo, which is fast, simple and easy to separate and purify. Novel single-point modified Exendin-4 derivative complex products for clinical application

Method used

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  • Composition of Exendin-4 derivative and preparation method and application thereof
  • Composition of Exendin-4 derivative and preparation method and application thereof
  • Composition of Exendin-4 derivative and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Example 1 Preparation of complexes of Exendin-4 derivatives.

[0045] In the first step, 1.0 mg of Exendin-4 derivative is dissolved in 1000 parts by weight of 10 mM, pH 3.0-9.0 phosphate buffer;

[0046] In the second step, add 5.7 mg of mPEG-MAL with a molecular weight of 5KD to the solution in the first step, and mix evenly;

[0047] In the third step, the solution in the second step is placed at 4-40°C for mPEG modification reaction for 0.5-24 hours;

[0048] In the fourth step, the solution treated in the third step is placed at -20°C to terminate the reaction, so far, the crude compound solution of the Exendin-4 derivative is obtained;

[0049] In the fifth step, the crude product solution prepared in the fourth step is diluted 10 times with 20 mM Tris-HCl buffer solution of pH 7.4, put on the Sepharose Q XL chromatography column, and then diluted with 20 mM Tris-HCl buffer solution containing 1-500 mM NaCl, pH 7.4 Gradient elution with Tris-HCl buffer, the flow...

Embodiment 2

[0053] Example 2 Preparation of complexes of Exendin-4 derivatives. In this example, the molecular weight of mPEG-MAL is 10KD.

[0054] In the first step, 1.0 mg of Exendin-4 derivative is dissolved in 1000 parts by weight of 10 mM, pH 3.0-9.0 phosphate buffer;

[0055] In the second step, add 11.4 mg of mPEG-MAL with a molecular weight of 10KD to the solution in the first step, and mix evenly;

[0056] The third step to the fifth step are carried out according to the corresponding operation steps in Example 1.

[0057] In the sixth step, the elution solution collected in the fifth step was concentrated with a Millipore Amicon Ultra15 ultrafiltration tube with a molecular weight cut-off of 1-10KD, and freeze-dried to obtain 1.35 mg of a complex of Exendin-4 derivatives with a molecular weight of 13.5KD pure goods.

Embodiment 3

[0058] Example 3 Preparation of Exendin-4 derivatives. In this example, the molecular weight of mPEG-MAL is 20KD.

[0059] In the first step, 1.0 mg of Exendin-4 derivative is dissolved in 1000 parts by weight of 10 mM, pH 3.0-9.0 phosphate buffer;

[0060] In the second step, add 22.8 mg of mPEG-MAL with a molecular weight of 20KD to the solution in the first step, and mix evenly;

[0061] The third step to the fifth step are carried out according to the corresponding operation steps in Example 1.

[0062] In the sixth step, the eluate collected in the fifth step was concentrated with a Millipore Amicon Ultra15 ultrafiltration tube with a molecular weight cut-off of 1 to 10 KD, and freeze-dried to obtain 2.35 mg of a complex of Exendin-4 derivatives with a molecular weight of 23.5 KD pure goods.

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Abstract

The invention discloses a composition of an Exendin-4 derivative and a preparation method and application thereof. The composition of the Exendin-4 derivative consists of the Exendin-4 derivative and mono-methyl polyethylene glycol activated by maleimide. The composition of the Exendin-4 derivative has high biostability, long half-life in vivo, and high bioavailability. The preparation method is easy and convenient to implement and raw materials are readily available.

Description

technical field [0001] The present invention relates to a modified Exendin-4 derivative, specifically, a complex of monomethoxypolyethylene glycol-Exendin-4 derivative and its preparation method and application, belonging to the modification of peptide or protein Technical field of complexes and their preparation. Background technique [0002] Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia caused by defects in insulin secretion and its biological function. At present, the morbidity and mortality of diabetes in my country are showing a rapid upward trend, and it has become another chronic non-communicable disease that seriously endangers people's health after cardiovascular and cerebrovascular diseases and tumors. More than 90% of them are type II diabetes. At present, people mainly use drugs such as sulfonylureas and biguanides to treat type II diabetes, but the side effects of these drugs are relatively large, which limits their clinical ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K1/107A61K38/22A61K47/48A61P3/10
Inventor 杨燕黄静张洪丹蒋子威劳勋吴自荣
Owner EAST CHINA NORMAL UNIV
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